The present invention relates to a treating agent against hepatitis C, in detail an anti-hepatitis C virus agent, a nucleic acid polymerase inhibitor, and a RNA-dependent RNA polymerase inhibitor.
It is supposed that there are one to two hundred million people infected with hepatitis C virus (hereafter called as HCV) worldwide, and over 1.5 million people infected with HCV in Japan. Approximately 50% of them become chronic hepatitis, and approximately 20% thereof become liver cirrhosis or hepatocellular carcinoma after 30 years or more of the infection. In Japan, twenty and several thousand people die every year due to hepatocellular carcinoma caused by HCV infection. At present, interferon xcex1 is used widely as a treating agent against hepatitis C, however, percentage of successful treatment is only 20% to 30% and its side effect is strong. It is expected to develop a more useful and more safety treating agent.
The anti-HCV agents are targeted on protease, RNA helicase, RNA-dependent RNA polymerase, and the like, and as the RNA-dependent RNA polymerase inhibitor known are cerulenin, gliotoxin, and dioxobutyric acid ((1) Antiviral Res., 41, 65 (1999), (2) Antiviral Ther., 3 (Suppl 3), 99 (1998), (3) WO00/06529).
On the other hand, as an acylthiazolidinedione derivative similar to a compound of the present invention, a compound wherein the acyl group is a substituted benzoyl group is described in (1) Strukt. Mekh. Deistviya Fiziol. Aktiv. Veschestv (1972) 92-92, (2) Khim. Geterotsikl. Soedin. (1972), (11), 1492-1495. However, in these references a concrete medical use is not described. Furthermore, a compound wherein the acyl group is a substituted heteroarylcarbonyl group is not; described therein at all.
The development of a treating agent against hepatitis C, especially an HCV RNA-dependent RNA polymerase inhibitor, is expected.
It is found that an acylthiazolidinedione derivative and the like have an HCV RNA-dependent RNA polymerase inhibitory effect.
That is, the present invention relates to:
(1) A treating agent against hepatitis C virus which contains as an active ingredient a compound of the formula (I), a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof: 
wherein R1 is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R2 and R3 taken together with the adjacent carbon atom form an optionally substituted heterocyclic group having one or more of oxo and/or thioxo,
(2) A treating agent against hepatitis C virus as described in (1) wherein R1 is optionally substituted heteroaryl or optionally substituted aryl; R2 and R3 taken together with the adjacent carbon atom form a group of the formula (A): 
wherein A1 and A3 are each independently oxygen atom or sulfur atom; A2 and A4 are each independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl,
(3) A treating agent against hepatitis C virus as described in (2) wherein A1 is oxygen atom; A2 is xe2x80x94NHxe2x80x94; A1 and A4 are sulfur atom,
(4) A compound of the formula (II): 
wherein R1 is optionally substituted carbocyclic group or optionally substituted heterocyclic group; A1 and A3 are each independently oxygen atom or sulfur atom; A2 is xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl, provided that when R1 is optionally substituted aryl, R4 is hydrogen or optionally substituted alkyl; A4 is xe2x80x94Sxe2x80x94; and provided that the following compounds are excluded wherein A1 is oxygen atom, A2 is xe2x80x94NEt-, A3 is sulfur atom, and R1 is 4-bromophenyl, 4-n-butoxycarbonylphenyl, 4-methoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3-methylphenyl, 4-methylphenyl, 4-chlorophenyl or phenyl; A1 is oxygen atom, A2 is xe2x80x94NHxe2x80x94, A3 is sulfur atom, and R1 is 2-thiocarboxyphenyl or 2-carboxyphenyl; and A1 is oxygen atom, A2 is xe2x80x94NHxe2x80x94, A1 is oxygen atom, and R1 is 2-carboxyphenyl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(5) A compound of (4) wherein R1 is optionally substituted heteroaryl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(6) A compound of (4) wherein R1 is non-substituted heteroaryl or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, trityl, alkoxyalkoxy, cyanoallylalkoxy, cyanoalkoxy, hydroxyalkyl, cyanoalkyl, carboxy or alkoxycarbonyl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(7) A compound of (5) or (6) wherein R1 is optionally substituted 5-membered heteroaryl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(8) A compound of (5) or (6) wherein R1 is optionally substituted furyl, optionally substituted t-hienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted tetrazolyl, optionally substituted pyridyl, optionally substituted benzofuryl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substitutec(thiazolyl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(9) A compound of (4) wherein R1 is optionally substituted aryl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(10) A compound of any one of (4) to (9) wherein A2 is xe2x80x94NHxe2x80x94;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(11) A compound of any one of (4) to (10) wherein A1 is oxygen atom; A3 is sulfur atom;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(12) A compound of any one of (4) to (9) wherein A1 is oxygen atom; A2 is xe2x80x94NHxe2x80x94; A3 is sulfur atom; A4 is xe2x80x94Sxe2x80x94;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(13) A pharmaceutical composition which contains as an active ingredient a compound of any one of (4) to (12), a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(14) A pharmaceutical composition of (13) as a treating agent against hepatitis C,
(15) A pharmaceutical composition of (13) as an anti-hepatitis C virus agent,
(16) A pharmaceutical composition of (13) as a nucleic acid polymerase inhibitor,
(17) A pharmaceutical composition of (13) as a RNA-dependent RNA polymerase inhibitor,
(18) A method of treating hepatitis C comprising administration of a treating agent against hepatitis C of (1),
(19) Use of a compound of (1) for the preparation of a treating agent against hepatitis C,
The present invention has found that a compound of the formula (I), a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof: 
wherein R1 is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R2 and R3 taken together with the adjacent carbon atom form an optionally substituted heterocyclic group having one or more of oxo and/or thioxo; exhibits an inhibitory effect against nucleic acid polymerase, in detail an inhibitory effect against RNA-dependent RNA polymerase, and inhibits the increase of HCV, whereby to provide a treating agent against HCV containing these compounds or the like.
A characteristic of the compounds used in the present invention is that the group represented by R1, and an optionally substituted heterocyclic group having one or more of oxo and/or thioxo which is formed by R2 and R3 taken together with the adjacent carbon atom are substituted on a group of the formula: 
Especially, as a compound of the formula (1) the following cases are preferred.
wherein R1 is optionally substituted heteroaryl or optionally substituted aryl,
wherein R1 is optionally substituted heteroaryl,
wherein R1 is non-substituted heteroaryl or heteroaryl optionally substituted with alkyl, alkoxy, hydroxy, halogen, trityl, alkoxyalkyl, cyanoarylalkoxy, cyanoalkoxy, hydroxyalkyl, cyanoalkyl, carboxy, or alkoxycarbonyl,
wherein R1 is optionally substituted 5-membered heteroaryl,
wherein R1 is optionally substituted furyl, optionally substituted thienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted tetrazolyl, optionally substituted pyridyl, optionally substituted benzofuryl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted thiazolyl,
wherein R1 is optionally substituted 5-membered aryl,
wherein R2 and R3 taken together with the adjacent carbon atom form a group of the formula (A): 
wherein A1 and A3 are each independently oxygen atom or sulfur atom; A2 and A4 are each independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl.
In a group shown by the above (A), preferred are those.
wherein A1 and A3 are each independently oxygen atom or sulfur atom; A2 is xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl; A4 is xe2x80x94Sxe2x80x94,
wherein A1 is oxygen atom; A2 is xe2x80x94NHxe2x80x94; A1 is sulfur atom; A4 is xe2x80x94Sxe2x80x94,
wherein A2 is xe2x80x94NHxe2x80x94,
wherein A1 is oxygen atom; A3 is sulfur atom, or
wherein A1 is oxygen atom; A2 is xe2x80x94NHxe2x80x94; A3 is sulfur atom; A4 is xe2x80x94Sxe2x80x94.
Especially, preferable is a compound of the formula (II): 
wherein R1 is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; A1 and A3 are each independently oxygen atom or sulfur atom; A2 is xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl, provided that when R1 is an optionally substituted aryl, R4 is hydrogen or optionally substituted alkyl; A4 is sulfur atom.
Each term employed alone or in combination with other terms has the following means.
The term xe2x80x9ccarbocyclic groupxe2x80x9d means cycloalkyl, cycloalkenyl, or aryl. Especially, aryl is preferred.
The term xe2x80x9ccycloalkylxe2x80x9d means a cycloalkyl having 3 to 10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cyclopentyl and cyclohexyl are preferred.
The term xe2x80x9ccycloalkenylxe2x80x9d means a cycloalkenyl having 3 to 10 carbon atoms. Examples of cycloalkenyl include 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl, 1-cyclooctenyl, and the like. 1-Cyclopentenyl and 1-cyclohexenyl are preferred.
The term xe2x80x9carylxe2x80x9d means monocyclic or condensed ring aromatic carbocyclic group having 6 to 14 carbon atoms. Examples of aryl include phenyl, 1-naphtyl, 2-naphtyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, and the like. Phenyl, 1-naphtyl, and 2-naphtyl are preferred.
The term xe2x80x9cherterocyclic groupxe2x80x9d for R1 means heteroaryl and non-aromatic herterocyclic group. Especially, heteroaryl is preferred.
The term xe2x80x9cheteroarylxe2x80x9d herein used means a 5 to 7 membered aromatic heterocyclic group which contains one or more of nitrogen, oxygen, and sulfur atoms in the ring, or an aromatic cyclic group fused with one or more aromatic carbocyclic group or other aromatic heterocyclic group. The xe2x80x9cheteroarylxe2x80x9d may have a bond ragical at any substitutable position, for example at a carbon or nitrogen atom in the aromatic heterocyclic group or aromatic carbocyclic group. Examples of the heteroaryl include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isotbiazolyl, 5-isothiazolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), furazanyl (e.g., 3-furazanyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzothienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzimidazolyl (e.g., 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinoxalinyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), phenazinyl (e.g., 1-phenazinyl, 2-phenazinyl), phenothiazinyl (e.g., 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl), and the like.
xe2x80x9c5-Membered heteroarylxe2x80x9d is preferred. Examples of the 5-membered heteroaryl include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), furazanyl (e.g., 3-furazanyl), and the like. Especially, are preferred furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), and the like.
The term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d herein used means a non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms in the ring, and the group has a bond radical at any substitutable position. Examples of the non-aromatic heterocyclic group include 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, oxazolinyl, and the like. Further, xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d may be saturated or unsaturated.
Further, xe2x80x9ccarbocyclic groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d for R1 may be fused additionally with a carbocycle or heterocycle. The term xe2x80x9ccarbocyclexe2x80x9d means carbocycle corresponding to the above mentioned xe2x80x9ccarbocyclic groupxe2x80x9d. Examples of carbocycle include cyclobutane, cyclopentane, cyclohexane, cycloheptane, benzene, naphthalene, and the like. The term xe2x80x9cheterocyclexe2x80x9d means heterocycle corresponding to the above mentioned xe2x80x9cheterocyclic groupxe2x80x9d. Examples of heterocycle are pyrrolidine, piperadine, oxolane, 1,3-dioxolane, 1,4-dioxolane, thiolane, thiophen, furan, pyrrole, pyridine, and the like.
These carbocycle and heterocycle may be fused additionally with carbocycle or heterocycle.
Examples of the above xe2x80x9ccarbocyclic groupxe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d which are fused with carbocycle or heterocycle are as follows. 
The term xe2x80x9cheterocyclic group having one or more oxo or thioxoxe2x80x9d means heterocyclic group having 1 to 3 oxo or thioxo at any possible position in the ring. Especially, 5- or 6-membered heterocyclic group having oxo or thioxo at a neighboring position of the bond radical is preferred and exemplified below. 
wherein A1 is each independently oxygen atom or sulfur atom; A5 is each independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl, or xe2x80x94CH2xe2x80x94, provided that one or more of A5 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl.
Among the above, preferable is a group represented by the formula (A): 
and more preferable is that wherein A1 and A3 are each independently oxygen atom or sulfur atom; A2 and A4 are each independently xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl.
Especially, preferable is a compound of the formula (II): 
wherein R1 is optionally substituted carbocyclic group or optionally substituted heterocyclic group; A1 and A3 are each independently oxygen atom or sulfur atom; A2 is xe2x80x94NR4xe2x80x94 wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl, provided that when R1 is optionally substituted aryl, R4 is hydrogen or optionally substituted alkyl; A4 is xe2x80x94Sxe2x80x94; and provided that the following compounds are excluded wherein A1 is oxygen atom, A2 is xe2x80x94NEt-, A3 is sulfur atom, and R1 is 4-bromophenyl, 4-n-butoxycarbonylphenyl, 4-methoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3-methylphenyl, 4-methylphenyl, 4-chlorophenyl or phenyl; A1 is oxygen atom, A2 is xe2x80x94NHxe2x80x94, A3 is sulfur atom, and R1 is 2-thiocarboxyphenyl or 2-carboxyphenyl; and A1 is oxygen atom, A2 is xe2x80x94NHxe2x80x94, A3 is oxygen atom, and R1 is 2-carboxyphenyl.
Substituents of xe2x80x9coptionally substituted alkylxe2x80x9d and xe2x80x9coptionally substituted acylxe2x80x9d include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, hydroxy, carboxy, formyloxy, formyl, haloformyl, oxalo, mercapto, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfamoyl, sulfoamino, optionally substituted amino, cyano, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, hydroxyamino, carbamoyl, nitroso, nitro, hydrazino, azide, ureido, amidino, guanidino, and the like. Especially, cycloalkyl, halogen, hydroxy, carboxy, optionally substituted amino, cyano, and the like are preferred. And unsubstituted one is preferred.
These substituents may be at 1 to 3 any substitutable position(s) in the above mentioned alkyl and the above mentioned acyl.
Substituents of xe2x80x9coptionally substituted carbocyclic groupxe2x80x9d, xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d, xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted aralkylxe2x80x9d and xe2x80x9coptionally substituted heteroarylxe2x80x9d include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, hydroxy, carboxy, formyloxy, formyl, haloformyl, oxalo, mercapto, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfamoyl, sulfoamino, optionally substituted amino, cyano, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, hydroxyamino, carbamoyl, nitroso, nitro, hydrazino, azide, ureido, amidino, guanidino, trityl, alkoxyalkyl, cyanoarylalkoxy, cyanoalkoxy, hydroxyalkyl, cyanoalkyl, carboxy, and alkoxycarbonyl, and the formula: xe2x80x94Z1-Z2 wherein Z1 is a single bond, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O).C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NZ3xe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94NZ3xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NZ3xe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94SO2xe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94, xe2x80x94NZ3xe2x80x94SO2xe2x80x94 or xe2x80x94SO2xe2x80x94NZ3xe2x80x94; Z2 and Z3 are each independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally substituted aminoalkyl, carbocyclic group optionally substituted with alkyl, hydroxy or halogen, heterocyclic group optionally substituted with alkyl, hydroxy or halogen, arylalkyl optionally substituted with alkyl, hydroxy or halogen, or heteroarylalkyl optionally substituted with alkyl, hydroxy or halogen, and the like. Especially, preferred are alkyl, alkoxy, hydroxy, halogen, trityl, alkoxyalkoxy, cyanoarylalkoxy, cyanoalkoxy, hydroxyalkyl, cyanoalikyl, carboxy and alkoxycarbonyl. And unsubstituted one is preferred.
These substituents may be at 1 to 5 any substitutable position(s) in the above mentioned carbocyclic group, the above mentioned heterocyclic group, the above mentioned aryl, the above mentioned aralkyl and the above mentioned heteroaryl.
The term xe2x80x9calkylxe2x80x9d herein used means a straight or branched chain alkyl having 1 to 8 carbon atom(s). Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, t-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonanyl, and the like.
The term xe2x80x9calkenylxe2x80x9d herein used means a straight or branched chain alkenyl having 2 to 8 carbon atoms and one or more double bonds. Examples of the alkenyl include vinyl, 1-propenyl, 2-propenyl, isopropenyl, and the like.
The term xe2x80x9clower alkynylxe2x80x9d herein used means a straight or branched chain alkynyl having 2 to 8 carbon atoms and one or more triple bond. Examples of the alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
Alkyl consisted in xe2x80x9calkoxyxe2x80x9d is defined as the above xe2x80x9calkylxe2x80x9d, examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like. Especially, methoxy and ethoxy are preferred.
The term xe2x80x9cacylxe2x80x9d herein used means carbonyl substituted with the above-mentioned xe2x80x9calkylxe2x80x9d and the above-mentioned xe2x80x9carylxe2x80x9d. Examples of acyl include acetyl, propyonyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, benzoyl, 1-naphthoyl, 2-naphthoyl, and the like. Especially, acetyl and benzoyl are preferred.
The term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo.
The term xe2x80x9chaloalkylxe2x80x9d herein used means the above-mentioned xe2x80x9calkylxe2x80x9d which is one or more substituted with halogen. Examples of the haloalkyl include chloromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dichloroethyl, and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d herein used means the above-mentioned xe2x80x9calkylxe2x80x9d which is one or two substituted with hydroxy. Examples of the hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,1-dihydroxyethyl, 1,2-dihydroxyethyl, 1,2-dihydroxy-n-propyl, and the like.
The term xe2x80x9caminoalkylxe2x80x9d herein used means the above-mentioned xe2x80x9calkylxe2x80x9d which is one or two substituted with amino. Examples of the aminoalkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl, 1,1-diaminoethyl, 1,2-diaminoethyl, 1,2-diamino-n-propyl, and the like.
Substituents of xe2x80x9coptionally substituted aminoxe2x80x9d and xe2x80x9coptionally substituted aminoalkylxe2x80x9d include, for example, the above-mentioned xe2x80x9calkylxe2x80x9d, the above-mentioned xe2x80x9carylalkylxe2x80x9d, the above-mentioned xe2x80x9ccarbocyclic groupxe2x80x9d, the above-mentioned xe2x80x9cheterocyclic groupxe2x80x9d, the above-mentioned xe2x80x9cheteroarylalkylxe2x80x9d, and the like. They may be mono- or di-substituted with these substituents. Further, when they are di-substituted with xe2x80x9calkylxe2x80x9d, may form a ring taken together nitrogen atom of amino group.
Examples of xe2x80x9coptionally substituted aminoxe2x80x9d include amino, methylamino, dimethylamino, methylethylamino, diethylamino, pyrrolidino, piperidino, phenylmethylamino, isopropylamino, diisopropylamino, and the like.
Examples of xe2x80x9coptionally substituted aminoalkylxe2x80x9d include aminomethyl, dimethylaminomethyl, methylaminomethyl, methylethylaminomethyl, diethylaminomethyl, pyrrolidinomethyl, piperidinomethyl, phenylmethylaminomethyl, isopropylaminomethyl, diisopropylaminomethyl, and the like.
The term xe2x80x9calkoxyalkoxyxe2x80x9d herein used means the above-mentioned alkoxy substituted with the above-mentioned alkoxy, examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, n-butoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy, and the like. Especially, methoxymethoxy and ethoxymethoxy are preferred.
The term xe2x80x9ccyanoarylalkoxyxe2x80x9d herein used means the above-mentioned alkoxy substituted the above-mentioned aryl substituted with cyano, examples of cyanoarylalkoxy include 2-cyanobenzyloxy and the like.
The term xe2x80x9ccyanoalkoxyxe2x80x9d herein used means the above-mentioned alkoxy substituted with cyano, examples of cyanoalkoxy include 3-cyano-n-propoxy and the like.
The term xe2x80x9ccyanoalkylxe2x80x9d herein used means the above-mentioned alkyl substituted with one to two cyano, examples of cyanoalkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1,1-dicyanoethyl, 1,2-dicyano-n-propyl, 3-cyano-n-propyl, and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d herein used means the carbonyl substituted with the above-mentioned xe2x80x9calkoxyxe2x80x9d, examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like. Especially, methoxycarbonyl and ethoxycarbonyl are preferred.